Contrast Agents. Altering Tissue Contrast. Altering Tissue Contrast

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1 Contrast Agents Mike Moseley, Ph.D. Department of Radiology Stanford University Current Concepts Monterey October 2005 Altering Tissue Contrast Intrinsic tissue contrasts: 1. uclei (proton) density - PD 2. Spin lattice Relaxation T1 3. Susceptibility T2* Are amenable for pharmacologic perturbation... Magnetic Susceptibility MR relaxation enhancement ("relaxivity") is a question of unpaired electrons... Diamagnetic agents no unpaired e- no effect on T1, T2. PD only 100 T1 - T2*- Paramagnetic agents unpaired e- 10 noninteracting domains T1 T2* Superparamagnetic unpaired e- pools 10 noninteracting domains T1 T2* rromagnetic unpaired e- oceans 10 strongly interacting domains T1-3 (>0.035µm) threshold... *cm / gauss T2* Oils, PFOB +3, +3 particle Metal Artifacts Altering Tissue Contrast -TR/T1 -TE/T2 SI = (H) [ 1 - e ] e 1. T1-shortening on T1w images. paramagnetic agents (-DTPA). coated supermagnetic irons (iron particles). 2. T2 (or T2*) shortening on T2*w images. para-/superparamagnetic agents (iron particles). paramagnetic agents (- or Dy-DTPA) Unpaired e - and T1 Relaxivity" Unpaired electron clouds fluctuate around metal. Create dipole-dipole effects (interactions with proton). Acts as magnetization sink draws magnetization. Promotes T1 relaxation shortens T1. Apparent shortening of proton T1- at a given B0 and temperature... 1/T1 (observed) = 1/ T1 (intrinsic) + R1 [Conc] ( 200 msec = 1000 msec + 3.8*[0.1mmol/kg] ) *mmol -1 L sec unpaired electrons T1, T2* +++ COOH -DTPA: Berlex Magnevist TM CH3-H-O O H-CH3 COOH -DTPA-BMA:ycomed-Amersham Omniscan TM +++ T1- Electron cloud relaxation T2* - Magnetic susceptibility -DOTA: Geurbet DOTAREM TM

2 Unpaired e- and T1 Relaxivity" has 7 unpaired e-+2) vs. DeOxy ( +3 +3) Oxy ( +2 -DTPA vs. Dy-DTPA -DTPA-binding Unpaired e- and T1 Relaxivity" Oxy vs. DeOxy -DTPA vs. Dy-DTPA -DTPA-binding 1/T1 (observed) (observed) = 1/ T1 (intrinsic) (intrinsic) + R1 [Conc] ( 200 msec = 1000 msec + 0.7[2mmol/kg] ) Unpaired e- and "Relaxivity" Oxy vs. -DTPA vs. Dy-DTPA -DTPA-binding Paramagnetics - Blood Pool Agents -phostriamine MS-325 -Epix - Schering T1-shortening agents: Affinity to HSA 80-90% labeled R T1/2 60minutes Conventional MRI Contrast-generating end Albumin-targeting end 10 Trr 1010 HSA Trr 1088 T1 Relaxivities mmol-1-1 L sec-1-1: -DTPA 4 -dimers 10 -Dextrans 40 MS-325-HSA 45 Iron oxides 20 Rabbit - Thrombus agent (EP-1242) visualizes on-occlusive arterial thrombus Targeted MR Agents: Polymerized P Vesicles for Detection and Therapy Lipid-based self-assembled system- Plasma life 16 hrs Vascular targeted gene delivery P with angiogenesis target Thrombus Pre-Contrast Post-Contrast Targeting Angiogen ligand Carotid Artery Blood Pool Epix Medical: E. Kent Yucel, Li Zhou, Brigham & Women s, Boston Bernardski, Bernardski, et et al. al. Molecular Molecular Imaging Imaging Lab, Lab, Stanford Stanford -DTPA ligands Polydiacetylene crosslink Drug Encapsulation

3 Unpaired e - and T1 Relaxivity" Oxy vs. -DTPA vs. Dy-DTPA -DTPA-binding MR Targeted Agents Open for Business Molecular (Genomic) imaging - Engineered -ligands e-gad mechanism Meade, et al. ature 2000 (II) Oxy (III) Unpaired e - and T1 Relaxivity" Oxy vs. -DTPA vs. Dy-DTPA -DTPA-binding Concentration of bolus (CE-MRA) Concentration of agent (GadovistTM) Unpaired e - and "Relaxivity" Concentration of agent (GadovistTM) R1 = T1 Relaxivities mmol -1 L sec -1 : -DTPA (0.5M) 4 Gadovist (1.0M) 8 Peripheral Run-off CE-MRA with a 1.0 Molar Gadolinium Chelate (Gadovist) with Intraarterial DSA Comparison. M. Gregor, B. Tombach, A. Hentsch, P. Reimer. GadovistTM -DTPA Unpaired e - and T2* Relaxivity" Magnetic susceptibility T2* Created by local gradients (of the unpaired electrons). Created by local environment (clots, RBC packing). Enhanced by proton diffusion through these gradients. Increased spin dephasing = T2* decreased. M Magnetic Susceptibility Affects Tissue Contrast gray-white matter tissue small gradient across sample present in brain... a shorter T2* M large gradient across sample Observed T2* Observed T2* TE TE

4 Blood = Ideal MR Contrast Agent? oxyhemoglobin O2 O2 Low ² χ Low ² χ O = O deoxygenates oxygenates deoxyhemoglobin 4 4 unpaired unpaired electrons electrons - - paramagnetic paramagnetic High High ² ² χ χ Unpaired e - and T2* Relaxivity" Oxy vs. deoxy - fmri Size and concentration of particle USPIO (blood pool) vs. SPIO (RES capture) R2* Relaxivity: 1/T2* (observed) = 1/ T2* (intrinsic) + R2* [Conc] ( 100 msec = 1000 msec + 6 [0.1mmol/kg] ) T2* Relaxivities (in order): Iron oxides Cl DyDTPA DTPA DeOxy Oxy ridex-enhanced MR USPIO Alterations of T1 and T2 Particulates (superparamagnetic irons): Possesses mild T1-shortening at low []. Large T2* effect at higher []. Biodistribution vary depending on size: >20 nm size Liver (RES) uptake agents 20 Oral (gut) agents Lymph nodes, blood pool 4-6 Hepatocytes, targets Size is the most important aspect of biodistribution. All particles must be < 5 µm to avoid entrapment in lung. Alterations of T1 and T2 Particulates (superparamagnetic irons): Lumiren - > 300nm (- agent) Abdoscan nm (- agent) Resovist nm (- agent) Sinerem - 40nm particle (-agent) C nm particle (+agent) Size is the most important aspect of biodistribution. All particles must be < 5 µm to avoid entrapment in lung. -Oxide (C GE-Amersham) Alterations of T1 and T2* T1-shortening is a short-range (1/r ) effect... Represents blood volume effect... Positive enhancement. Effect no larger than T1-differences. Small enhancement in intact BBB. 6 T2*-shortening is a long-range (B0) effect... Local field alterations extend over µm-mm. Pronounced effect in brain. Potent mechanism. Image quality and scan time issues.

5 Paramagnetic Contrast on T1, T2* Concentration effects T1-shortening effect Paramagnetic Contrast on T2* Intensity and Agent Concentration 1/T2* (observed) = 1/ T2 (intrinsic) + R2* [Conc] ( 50 msec = 1000 msec + 6[0.1mmol/kg] ) SI T2*-shortening effect Bolus -DTPA : T2* 50 msec SI slice bolus capillary bed white matter mmol/kg [] gray matter (greater rcbv) seconds ECF +3-chelates Oral Type of Agent abdomen and pelvis Organ Specifc Liver and lymph Blood Pool Persistent Contrast Agent Families Approved Dotarem (Guerbet) Magnevist (Berlex) Omniscan (Amersham) ProHance (Bracco) Abdoscan (Amersham) Imagent GI LumenHance (Bracco) Lumirem/ Entera Endorem/ridex Teslascan Comments Abdoscan - OMP < 300nm (-) Imagent - Alliance PFOB $200 (-) Lumenhance MnCl (+ agent) Lumiren - AMI-121 iron oxide > 300nm (-) Endorem - AMI nm (-) Teslascan AMI - MnDPDP (+) AngioMARK (MS-325) Schering C ECF +3-chelates Oral Type of Agent abdomen and pelvis Organ Specifc Liver and lymph Blood Pool Persistent Contrast Agents and the Market ot Yet Approved Gadovist Multihance Gadolite Eovist Resovist Sinerem/Combidex/ri dex/gastromark AngioMARK (MS-325) Sinerem/Combidex MultiHance C Comments Gadovist- 1Molar DTPA Schering MultiHance 5% hepata-activity (+) Bracco Gadolite Pharmacyclics (+) Dendrimer, caged Eovist-EOB-DTPA Schering (+) Resovist- Iron oxide (-) Schering Sinerem family - Iron oxides (-) AMI227 40nm particle Epix- First true specific agent (+) C Clariscan 20nm (+) Blood = Ideal MR Contrast Agent? oxyhemoglobin O = O deoxyhemoglobin O2 O2 Low ² Low χ ² χ deoxygenates oxygenates 4 unpaired electrons - - paramagnetic High ² χ χ

6 Capillary Structure Creates a Local MR Gradient - Causes Proton Dephasing......any changes in delivery of O2 causes changes in image intensity... O2: low χ : high χ O2: low χ : high χ Balance of O2 to affects T2*. T2* effects extend beyond vascular space. Surplus of O2 to leads to a increase in T2*-weighted image intensity...